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A stochastic model correctly predicts changes in budding yeast cell cycle dynamics upon periodic expression of CLN2.

Oguz C, Palmisano A, Laomettachit T, Watson LT, Baumann WT, Tyson JJ - PLoS ONE (2014)

Bottom Line: Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model.We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression.These cells originate from daughters with extended budded periods due to size control during the budded period.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT
In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast.

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Budding index trajectories under different conditions.Simulation results. Evolution of the budding index (fraction of budded cells in a cell population at a given time) for the unforced cells (cln3, green lines) and the cells with forced CLN2 expression (cln3 MET3-CLN2, black lines). Forcing period is 90 min in (A), 78 min in (B), and 69 min in (C). Each individual trajectory represents a pedigree initiated by a single daughter cell, three trajectories are shown per forcing period. Blue shaded areas represent the time intervals in which MET3-CLN2 is active (time lag for the MET3 promoter turn on/off is taken into account).
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pone-0096726-g003: Budding index trajectories under different conditions.Simulation results. Evolution of the budding index (fraction of budded cells in a cell population at a given time) for the unforced cells (cln3, green lines) and the cells with forced CLN2 expression (cln3 MET3-CLN2, black lines). Forcing period is 90 min in (A), 78 min in (B), and 69 min in (C). Each individual trajectory represents a pedigree initiated by a single daughter cell, three trajectories are shown per forcing period. Blue shaded areas represent the time intervals in which MET3-CLN2 is active (time lag for the MET3 promoter turn on/off is taken into account).

Mentions: Figure 3B shows that 78 min period pulses result in higher synchrony (more “step-function” like budding index trajectories) than 90 and 69 min period pulses (Figures 3A and 3C), whereas without any pulse (cln3) cell populations lack synchrony: the budding index settles around 0.5 (half of the population budded) after about 300 min. Later, we will quantitatively show that 78 min is the optimal period for synchronizing budding yeast cells among these three period values. Intuitively, this can be explained in terms of the observed mother and daughter natural cycle times without forced CLN2 expression: pulses with a period of 69 min come much faster than the natural cycle time of daughter cells (94 min), and pulses with a period of 90 min come much slower than the natural cycle time of mother cells (71 min). The 78 min pulse period is midway between these cycle times, leading to good overall synchrony within the population compared to 90 and 69 min periods. We note that Figure 3B (evolution of budding index with 78 min pulse period) is in good qualitative agreement with Figure 1D in [7].


A stochastic model correctly predicts changes in budding yeast cell cycle dynamics upon periodic expression of CLN2.

Oguz C, Palmisano A, Laomettachit T, Watson LT, Baumann WT, Tyson JJ - PLoS ONE (2014)

Budding index trajectories under different conditions.Simulation results. Evolution of the budding index (fraction of budded cells in a cell population at a given time) for the unforced cells (cln3, green lines) and the cells with forced CLN2 expression (cln3 MET3-CLN2, black lines). Forcing period is 90 min in (A), 78 min in (B), and 69 min in (C). Each individual trajectory represents a pedigree initiated by a single daughter cell, three trajectories are shown per forcing period. Blue shaded areas represent the time intervals in which MET3-CLN2 is active (time lag for the MET3 promoter turn on/off is taken into account).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016136&req=5

pone-0096726-g003: Budding index trajectories under different conditions.Simulation results. Evolution of the budding index (fraction of budded cells in a cell population at a given time) for the unforced cells (cln3, green lines) and the cells with forced CLN2 expression (cln3 MET3-CLN2, black lines). Forcing period is 90 min in (A), 78 min in (B), and 69 min in (C). Each individual trajectory represents a pedigree initiated by a single daughter cell, three trajectories are shown per forcing period. Blue shaded areas represent the time intervals in which MET3-CLN2 is active (time lag for the MET3 promoter turn on/off is taken into account).
Mentions: Figure 3B shows that 78 min period pulses result in higher synchrony (more “step-function” like budding index trajectories) than 90 and 69 min period pulses (Figures 3A and 3C), whereas without any pulse (cln3) cell populations lack synchrony: the budding index settles around 0.5 (half of the population budded) after about 300 min. Later, we will quantitatively show that 78 min is the optimal period for synchronizing budding yeast cells among these three period values. Intuitively, this can be explained in terms of the observed mother and daughter natural cycle times without forced CLN2 expression: pulses with a period of 69 min come much faster than the natural cycle time of daughter cells (94 min), and pulses with a period of 90 min come much slower than the natural cycle time of mother cells (71 min). The 78 min pulse period is midway between these cycle times, leading to good overall synchrony within the population compared to 90 and 69 min periods. We note that Figure 3B (evolution of budding index with 78 min pulse period) is in good qualitative agreement with Figure 1D in [7].

Bottom Line: Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model.We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression.These cells originate from daughters with extended budded periods due to size control during the budded period.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT
In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast.

Show MeSH
Related in: MedlinePlus